Project 5: S. Lowe Tumor Suppression Hannon, Gregory J PROJECT SUMMARV (See instructions): This project studies tumor-suppressor gene (TSG) networks and how their disruption influences malignant behavior. Initially based on its observation that oncogenes can activate p53 to promote apoptosis, our early efforts involved studying mechanisms whereby p53 drives apoptosis and how suppression of p53 effectors or deregulated survival signaling can circumvent during promote tumorigenesis. Over the last funding cycle, we identified several new regulators of oncogene-induced apoptosis that contribute to tumorigenesis and validated translational control of cell survival as a therapeutic target. Taking advantage of inducible RNAi technology we developed with Greg Hannon, we also showed that reactivation of endogenous p53 in tumors potently triggered apoptosis or senescence depending on context, thus establishing a role for p53 loss in tumor maintenance. Finally, exploiting unique features of the mouse models developed in the program we, through candidate gene testing and in vivo screens, identified and validated several new oncogenes and over 35 new TSGs that are relevant to human cancer. Moving forward, the project will continue to innovate at both the biological and technical levels, taking a more comprehensive approach towards studying tumor suppressors, with a particular focus on their action in gastrointestinal malignancies and an eye towards developing new therapeutic targets. Specifically, we will identify and characterize new TSGs in several gastrointestinal malignancies, study the role of extremely common but poorly understood large chromosomal deletions on cancer development, explore the action of key TSGs in tumor maintenance, and perform negative selection RNAi screens to identify and then characterize potential vulnerabilities created by TSG loss. Experimentally, we will take advantage of genomic analyses of human gastrointestinal cancers to inform functional studies in mice, and implement a suite of new RNAi tools and animal modeling approaches to increase the cost effectiveness and pace of our analyses. Successful completion of these studies will identify new genes relevant to human gastrointestinal malignancies and determine how they influence disease behavior. Our efforts may also identify new therapeutic targets for treating cancers with TSG mutations, which have otherwise been difficult to exploit therapeutically. In addressing these aims, our project will produce a blueprint that can be applied to other genes and tumor types. Our goal is to gain a more comprehensive understanding of tumor suppressor networks and identify therapeutic targets relevant to specific cancer genotypes.